PMID- 23418425
OWN - NLM
STAT- MEDLINE
DCOM- 20130809
LR  - 20221207
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 2
DP  - 2013
TI  - Detection and clinical significance of intratumoral EGFR mutational heterogeneity 
      in Chinese patients with advanced non-small cell lung cancer.
PG  - e54170
LID - 10.1371/journal.pone.0054170 [doi]
LID - e54170
AB  - PURPOSE: This study evaluated occurrence and potential clinical significance of 
      intratumoral EGFR mutational heterogeneity in Chinese patients with non-small 
      cell lung cancer (NSCLC). MATERIALS AND METHODS: Eighty-five stage IIIa-IV NSCLC 
      patients who had undergone palliative surgical resection were included in this 
      study. Of these, 45 patients carried EGFR mutations (group-M) and 40 patients 
      were wild-type (group-W). Each tumor sample was microdissected to yield 28-34 
      tumor foci and Intratumoral EGFR mutation were determined using Denaturing High 
      Performance Liquid Chromatography (DHPLC) and Amplification Refractory Mutation 
      System (ARMS). EGFR copy numbers were measured using fluorescence in situ 
      hybridization (FISH). RESULTS: Microdissection yielded 1,431 tumor foci from EGFR 
      mutant patients (group-M) and 1,238 foci from wild-type patients (group-W). The 
      EGFR mutant frequencies in group-M were 80.6% (1,154/1,431) and 87.1% 
      (1,247/1,431) using DHPLC and ARMS, respectively. A combination of EGFR-mutated 
      and wild-type cells was detected in 32.9% (28/85) of samples by DHPLC and 28.2% 
      (24/85) by ARMS, supporting the occurrence of intratumoral heterogeneity. 
      Thirty-one patients (36.5%) were identified as EGFR FISH-positive. Patients 
      harboring intratumoral mutational heterogeneity possessed lower EGFR copy numbers 
      than those tumors contained mutant cells alone (16.7% vs. 71.0%, P<0.05). Among 
      26 patients who had received EGFR-TKIs, the mean EGFR mutation content was higher 
      in patients showing partial response (86.1%) or stable disease (48.7%) compared 
      with patients experiencing progressive disease (6.0%) (P = 0.001). There also 
      showed relationship between progression-free survival (PFS) and different content 
      of EGFR mutation groups (pure wild type EGFR, EGFR mutation with heterogeneity 
      and pure mutated EGFR) (P = 0.001). CONCLUSION: Approximately 30% of patients 
      presented intratumoral EGFR mutational heterogeneity, accompanying with 
      relatively low EGFR copy number. EGFR mutant content was correlated with the 
      response and prognosis of EGFR-TKIs.
FAU - Bai, Hua
AU  - Bai H
AD  - Key Laboratory of Carcinogenesis and Translational Research Ministry of 
      Education, Department of Thoracic Medical Oncology, Peking University Cancer 
      Hospital & Institute, Beijing, China.
FAU - Wang, Zhijie
AU  - Wang Z
FAU - Wang, Yuyan
AU  - Wang Y
FAU - Zhuo, Minglei
AU  - Zhuo M
FAU - Zhou, Qinghua
AU  - Zhou Q
FAU - Duan, Jianchun
AU  - Duan J
FAU - Yang, Lu
AU  - Yang L
FAU - Wu, Meina
AU  - Wu M
FAU - An, Tongtong
AU  - An T
FAU - Zhao, Jun
AU  - Zhao J
FAU - Wang, Jie
AU  - Wang J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130213
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.7.10.1 (EGFR protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Asian People/genetics
MH  - Biomarkers, Tumor/genetics
MH  - Carcinoma, Non-Small-Cell Lung/drug therapy/*genetics/pathology
MH  - China
MH  - DNA Mutational Analysis
MH  - Disease-Free Survival
MH  - ErbB Receptors/*genetics
MH  - Female
MH  - Humans
MH  - Lung Neoplasms/drug therapy/*genetics/pathology
MH  - Male
MH  - Middle Aged
MH  - *Mutation
MH  - Prognosis
MH  - Protein Kinase Inhibitors/therapeutic use
MH  - Treatment Outcome
PMC - PMC3572159
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2013/02/19 06:00
MHDA- 2013/08/10 06:00
PMCR- 2013/02/13
CRDT- 2013/02/19 06:00
PHST- 2012/08/21 00:00 [received]
PHST- 2012/12/07 00:00 [accepted]
PHST- 2013/02/19 06:00 [entrez]
PHST- 2013/02/19 06:00 [pubmed]
PHST- 2013/08/10 06:00 [medline]
PHST- 2013/02/13 00:00 [pmc-release]
AID - PONE-D-12-25047 [pii]
AID - 10.1371/journal.pone.0054170 [doi]
PST - ppublish
SO  - PLoS One. 2013;8(2):e54170. doi: 10.1371/journal.pone.0054170. Epub 2013 Feb 13.